Author + information
- Received September 2, 2017
- Accepted October 3, 2017
- Published online December 4, 2017.
- Yoshio Takemoto, MD, PhDa,b,
- Rafael J. Ramirez, PhDb,
- Kuljeet Kaur, PhDb,
- Oscar Salvador-Montañés, MDb,
- Daniela Ponce-Balbuena, PhDb,
- Roberto Ramos-Mondragón, PhDb,
- Steven R. Ennis, PhDb,
- Guadalupe Guerrero-Serna, PhDb,
- Omer Berenfeld, PhDb and
- José Jalife, MDb,c,∗ ()
- aDepartment of Cardiovascular Medicine, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
- bDepartment of Internal Medicine, Center for Arrhythmia Research, University of Michigan, Ann Arbor, Michigan
- cCentro Nacional de Investigaciones Cardiovasculares Carlos III and CIBERCV, Madrid, Spain
- ↵∗Address for correspondence:
Dr. José Jalife, Center for Arrhythmia Research, University of Michigan, 2800 Plymouth Road, Ann Arbor, Michigan 48109.
Background The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of atrial fibrillation (AF) in patients with systolic heart failure, but the mechanism is unknown.
Objectives This study hypothesized that by reducing atrial dilation and fibrosis in the absence of heart failure, EPL also reduces AF burden and prevents AF perpetuation.
Methods The authors conducted a randomized controlled study in 34 sheep that were atrially tachypaced (13 ± 1 week). They compared daily oral EPL (n = 19) versus sugar pill (SP) treatment (n = 15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (n = 29) or completion of 23 weeks tachypacing (n = 5).
Results EPL significantly reduced the rate of left atrial dilation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis, and cell hypertrophy than SP-treated sheep atria did. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but rather prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility, and AF burden.
Conclusions In the sheep model, EPL mitigates fibrosis and atrial dilation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.
Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with an increased risk of stroke, heart failure (HF), and dementia (1–4). Nonparoxysmal AF (including persistent and permanent AF) increases the risk of thromboembolism and death, which calls for development of new upstream therapies to prevent AF progression (5). Atrial dilation, fibrosis, and electrical remodeling underlie the transition from paroxysmal to persistent AF (6) and contribute to AF perpetuation. Recently we demonstrated that targeting the profibrotic protein galectin (Gal)-3 using a relatively low intravenous dose of the galactomannan GM-CT-01 (GMCT) (7) reduces both structural and electrical remodeling as well as AF burden in a sheep model of persistent AF in the absence of comorbidities (8). However, Gal-3 inhibition did not restore sinus rhythm in the long term (8). Nevertheless, our study provided a solid proof of concept in support of upstream AF prevention therapy.
Mineralocorticoid receptor blockers (MRBs) are beneficial in systolic HF (9–11). Specifically, the MRB eplerenone (EPL) has been shown to reduce new onset AF and recurrent AF in HF patients (12). Both angiotensin II and aldosterone elevations may lead to atrial fibrosis and contribute to human AF (13). Experimental results suggest that aldosterone may cause a substrate for atrial fibrosis and AF (14). Aldosterone increases the expression of 11β-hydroxysteroid dehydrogenase type 2 (11b-HSD2) leading to up-regulation of profibrotic mediators and collagen synthesis, which is prevented by MRBs (15).
Here we have investigated whether EPL prevents structural and electrophysiological remodeling, and reduces AF burden in our sheep model of persistent AF (16). In addition, we have determined whether EPL is a potentially effective upstream therapy to prevent persistent AF.
An expanded methods section is available in the Online Appendix.
Protocol for the blinded randomized-controlled study in sheep
All procedures complied with National Institutes of Health guidelines. A total of 34 male sheep (35 to 40 kg) underwent subcutaneous pacemaker implantation with a lead attached to the right atrial (RA) appendage (8,16). An implantable loop recorder was inserted parasternally in close apposition to the left atrium (LA). After 1-month recovery, sheep were randomized to: 1) a sugar pill (SP)–treated AF control group (n = 15); or 2) an EPL-treated AF group (100 mg/day orally; n = 19). We also used 6 sham-operated animals from previous studies as a reference control group (8,16). The time from pacemaker implantation to terminal assessment was 108.4 ± 11.4 days in SP-treated animals, 125.3 ± 10.9 days in EPL-treated animals, and 193 ± 45.5 days in sham-operated animals. Investigators were blinded to the randomization. Animals were euthanized after 7 days of self-sustained AF without pacing (7-day persistent AF [7d-PeAF]) followed by 1-week observation and terminal ex vivo and in vitro experiments. Sheep that did not reach 7d-PeAF during 23 weeks of tachypacing were euthanized at week 24.
AF progression and follow-up
Data were collected weekly from pacemakers, implantable loop recorders, and body surface electrocardiography standard lead II. Power spectral analysis was used to measure dominant frequency (DF) of atrial activation from the intracardiac RA lead and far-field LA signals during AF episodes. Atrial dimensions, mitral and tricuspid regurgitation, ejection fraction, and ventricular and septal dimensions were evaluated echocardiographically every 2 weeks.
Normally distributed data are expressed as mean ± SEM, where n represents the number of animals. See the Online Appendix for further details.
AF progression in the sheep model is characterized by continuously increasing markers of electrophysiological and structural remodeling, as well as AF burden, until AF becomes persistent (8,16). To determine whether EPL interferes with such changes, we randomized 34 sheep into daily oral EPL (100 mg; n = 19) or SP (n = 15) treatment (Online Figure 1). We defined 5 time points from the start of tachypacing: 1) first AF episode (1st-AF); 2) first 12-h AF episode (12h-AF); 3) first 1-day AF episode; 4) first continuous 7-day stretch of persistent AF (7d-PeAF); and 5) terminal.
Body weight increased similarly with time in EPL-treated and SP-treated animals (Online Figure 2). No animals developed HF or stroke. On lead II electrocardiography, neither EPL treatment nor SP treatment altered the QT or QTc interval measured at baseline and at final evaluation (Online Figure 3).
EPL mitigates atrial dilation and cell elongation during AF progression
Echocardiographically measured left ventricular ejection fraction and left ventricular end-diastolic volume were unchanged with respect to baseline in both SP-treated and EPL-treated groups (Online Figures 4A to 4C). In contrast, the AF-associated increase in end-systolic LA area was significantly attenuated in EPL-treated animals compared with SP-treated animals at 12h-AF, first 1-day AF episode, and 7d-PeAF (Figure 1A). At 7d-PeAF end-systolic RA and LA areas were visibly smaller in the sham-operated group than in the other 2 groups. Throughout AF progression, mitral and tricuspid regurgitation in EPL- and SP-treated hearts were similar (Figure 1B, Online Figure 4D). At final evaluation, there was no significant difference in adjusted atrial tissue weight (Figure 1C), but adjusted endocardial LA and posterior left atrial (PLA) areas measured directly in explanted hearts were reduced in the EPL-treated group compared with the SP-treated group (Figure 1D). Myocyte length was significantly less in the EPL-treated group than in the SP-treated group, but myocyte widths were similar (Figure 1E). Lengths of RA and LA myocytes from the sham-operated group were consistently smaller than those from the other 2 groups.
EPL reduces atrial fibrosis
Fibrosis in the LA, PLA, and RA was significantly less in EPL-treated tissues than in SP-treated tissues as determined by picrosirius staining (Figures 2A and 2B). The results correlated well with decreased terminal serum levels of procollagen type III N-terminal propeptide (P3NP) in EPL-treated animals compared with SP-treated animals (Figure 2C) (17). Further, on Western blotting of atrial tissue lysates, smooth muscle actin (SMA) protein and collagen III (COLIII) expression were also 32% and 35% lower, respectively, in the EPL-treated sheep than in SP-treated sheep (Figures 2D and 2E). Finally, in cultured sheep atrial myofibroblasts, proliferation assay data show that aldosterone increased the number of atrial myofibroblasts at 2 different concentrations (Online Figure 5).
EPL-induced mitigation of atrial dilation and fibrosis is not mediated through altered mineralocorticoid receptor expression
Previous studies have shown up-regulation of mineralocorticoid receptor (MR) in AF (13). The MR is the nuclear aldosterone receptor responsible for the genomic effects of aldosterone. 11b-HSD2 inactivates cortisol and corticosterone, allowing aldosterone to activate the MR (18). We investigated whether AF or MR blockade by EPL altered MR (NR3C2) or 11b-HSD2 (HSD11B2) gene expression in sheep LA tissue, or aldosterone levels in serum of sham-operated, SP-treated, and EPL-treated sheep. In Figure 2F, NR3C2 expression was slightly increased in EPL-treated animals compared with SP-treated animals, but the difference was not significant. HSD11B2 was significantly increased in EPL-treated sheep compared with SP-treated sheep (Figure 2G). 11b-HSD2 converts active cortisol to inactive cortisone, which is thought to reduce MR activation similar to EPL. Thus, in EPL-treated animals, EPL likely inhibited MR activation 2 different ways: 1) by directly binding competitively to MR; and 2) by increasing HSD11B2 expression, thus increasing 11b-HSD2 protein, which increased cortisone binding to and inhibiting the activity of MR. Finally, as expected (19), serum aldosterone levels were increased in SP-treated AF sheep compared with sham-operated sheep (Figure 2G). EPL treatment tended to decrease the serum aldosterone level, yet there was no significant difference between the SP-treated animals and EPL-treated animals.
EPL fails to prevent electrical remodeling during AF progression
The rate of increase in DF in the EPL-treated group was similar to the SP-treated group both in RA and LA (Figure 3A). At final ex vivo evaluation by optical mapping, AF was successfully reinduced by electrical pacing in all Langendorff-perfused hearts and did not spontaneously cardiovert to sinus rhythm before the end of experiment. Regional maximum DF was recorded optically every 2 min from the PLA, LA, and RA. As expected, regional maximum DF was always larger in the PLA and the LA than the RA, but was similar for EPL-treated and SP-treated groups in all atrial regions (Figure 3B). In phase movies we counted the number of phase singularity points, the number of visible rotors per second, and the frequency of rotations. Rotor frequency and number of rotors were similar in EPL-treated and SP-treated hearts (Figures 3C and 3D).
Upon restoration of stable sinus rhythm by electrical shock in the Langendorff-perfused hearts we conducted action potential duration (APD) restitution experiments to determine whether EPL had prevented the previously demonstrated persistent AF-induced shortening of the optically mapped action potential (8). Mean APD at 90% repolarization was similar in EPL-treated and SP-treated hearts at all cycle lengths tested (Figure 3E). In addition, conduction velocity and wavelength (APD at 90% repolarization × conduction velocity) during pacing were indistinguishable between EPL-treated and SP-treated groups in both the LA and RA (Figure 3F, Online Figures 6 and 7). Moreover, in isolated LA and RA myocytes from persistent AF animals, inward rectifier potassium current (IK1) and L-type calcium current (ICaL) were not significantly different between EPL-treated and SP-treated animals (Figures 4A and 4B). IK1 and ICaL data were consistent with similar Kir2.3 and CaV1.2 protein expression levels in both groups. Thus, EPL treatment had no effect on the previously demonstrated persistent AF-induced changes in Kir2.3 and CaV1.2 protein expression (8) when compared with changes seen in SP-treated animals (Figure 4C). Altogether, these results demonstrate that EPL treatment does not modify persistent AF-related electrical remodeling at the whole-animal, organ, cellular, or molecular levels.
EPL treatment reduces AF wave complexity
Both atrial stretch and fibrosis are known to be associated with persistent AF (20,21). In addition, the patterns of wave propagation in the fibrotic atria with persistent AF are more complex than in atria undergoing paroxysmal AF (8). Therefore, we hypothesized that by effectively reducing both atrial dilation and interstitial fibrosis EPL modifies AF source dynamics in such a way as to reduce the complexity of wave propagation (fibrillatory conduction). We therefore used phase movies (22) to analyze AF dynamics in the PLA, LA, and RA by counting the number of singularity points, the number of their rotations, their life spans, and the length of their trajectories (Figure 5) (23). As shown previously, the rotor frequency was similar in SP-treated and EPL-treated hearts (Figure 3C). In addition, the number of singularity points (Online Figure 8) and their life spans (Figure 5B) were also similar between treatment groups. However, the average lengths of the individual rotor trajectories adjusted to the number of rotations were significantly smaller in EPL-treated hearts than in SP-treated hearts (Figure 5C). Altogether, the foregoing results suggest strongly that by preventing interstitial fibrosis throughout the atria, EPL treatment contributed to a substrate where rotors could anchor to inscribe simpler trajectories. However, by failing to prevent electrical remodeling, the drug failed to alter the number, rotation frequency, and life span of AF sources.
EPL prolongs the progression of AF and reduces AF burden and inducibility
EPL treatment significantly prolonged the time from start of tachypacing to 12h-AF in EPL-treated animals compared with SP-treated animals (Figure 6A) (p = 0.041). EPL treatment also reduced the percentage of animals with sustained AF for more than 7 days within 23 weeks from the onset of tachypacing by 26% (Figure 6C) (p = 0.04, Fisher exact test).
We define AF burden as the percentage of self-sustained AF over a given time. AF burden during AF progression follows a Hill regression in both treatment groups (R2 = 0.52 and 0.59, respectively) (Figure 6D). EPL treatment substantially shifted the curve to the right, indicating relief of AF burden. Time to 50% AF burden, calculated individually by sigmoidal fitting, was 42.5% greater in EPL-treated sheep than in SP-treated sheep (p = 0.027) (Figure 6E). AF inducibility index, which was calculated as the inverse of the number of pacing attempts to reinduce AF, also followed a Hill regression (R2 = 0.62 and 0.55, respectively). EPL treatment also shifted the curve of AF inducibility index to right (Figure 6F), and increased the time to 50% AF inducibility index by 43.7% (p = 0.021) (Figure 6G), indicating a reduction in inducibility. These results indicate that EPL treatment significantly changed vulnerability to AF during AF progression. EPL treatment tended to prolong the total pacing time throughout the study compared with SP-treated animals, but did not change the total sustained AF time without tachypacing (Online Figure 9).
The most important results of this study are the following (Central Illustration): 1) EPL treatment mitigated structural remodeling including atrial dilation, myocyte hypertrophy, serum P3NP, tissue levels of SMA and COLIII, and fibrosis during the transition to tachypacing-induced persistent AF; 2) EPL treatment failed to prevent or even reduce the increase in DF, the decrease in APD and Cav1.2 (ICaL), and the increase in Kir2.3 (IK1) that reflect electrical remodeling during AF progression (8); 3) EPL treatment decreased AF wave complexity, AF inducibility, and AF burden, but delayed the onset of persistent AF only in 26% of animals.
The renin-angiotensin-aldosterone system is involved in atrial electroanatomical remodeling and is likely to mediate the development of atrial fibrosis and the progression of AF to more permanent forms (6) For example, angiotensin-converting enzyme inhibition was shown to suppress atrial fibrosis and the development of persistent AF in an animal model of atrial tachypacing and left ventricular dysfunction (24). Also clinical studies have reported a lower incidence of AF in selected patient populations treated with renin-angiotensin-aldosterone system inhibitors compared with control patients (25). AF is also less likely to recur after cardioversion in patients treated with renin-angiotensin-aldosterone system inhibitors than in control patients. New onset AF in patients with significant underlying heart disease was reduced with angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, but there is a lack of robust evidence in patients with mild to moderate structural heart disease (26).
In addition to the traditional angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, MRBs also have been shown to effectively reduce the incidence of new onset AF in systolic HF and to have beneficial effects on mortality in patients with cardiac disease (12). In the ventricular pacing–induced congestive HF dog model, MRB suppresses inducibility of sustained atrial tachyarrhythmias and attenuates left ventricular diastolic remodeling (27). Our experimental results show clearly that EPL significantly mitigates structural remodeling during the transition to persistent AF. Animals treated with EPL had significantly smaller atrial size, and less cellular hypertrophy and fibrosis than did SP-treated animals. Atrial size is an important determinant of clinical AF. Myocyte hypertrophy was also diminished by EPL. Our data are consistent with studies in mouse models in which deletion or inactivation of the MR gene attenuated left ventricular dilation, hypertrophy, and development of HF, whereas MR overexpression in cardiomyocytes induced ventricular remodeling, HF, and arrhythmias (28,29).
EPL treatment did not have any substantial effect on electrical remodeling reflected by DF increase and APD shortening during AF progression. The results are different from those previously obtained by the use of the Gal-3 inhibitor GMCT (8), which, unlike EPL, prevented the sustained AF-induced APD shortening in both the RA and LA, and prevented the sustained AF-induced increase in Kir2.3 expression and IK1 density in the same model of tachypacing-induced persistent AF. On the other hand, similar to EPL, Gal-3 inhibition mitigated structural remodeling, and both drugs significantly reduced AF complexity, AF inducibility, and AF burden, see Takemoto et al. (8) and Figure 6.
The question of which is the most important factor underlying the pathophysiology of AF progression and perpetuation is still being debated. In this study, EPL treatment significantly attenuated structural remodeling of the LA (Figure 4), whereas electrical remodeling progressed equivalently at corresponding time points in both treatment groups during AF progression (Figure 3). Because 7d-PeAF was delayed only in 26% of animals (Figure 6B), the results presented here, together with the slowing of ion channel remodeling demonstrated previously in GMCT-treated animals (8), highlight the significance of electrical remodeling in AF perpetuation. However, it is important to note that although structural remodeling was attenuated by EPL treatment, it was not completely prevented, indicating that there might still exist a minimum requirement of structural remodeling, which together with advanced electrical remodeling contributes to AF perpetuation. In addition, the reduced AF burden and AF inducibility promoted by EPL (Figures 6D–G) clearly support the contention that structural remodeling is important. Therefore, although our results do not fully resolve the issue of which of these 2 factors is the most important, the data strongly suggest that both contribute and act in synergy to promote AF perpetuation. The target for the antifibrotic action of EPL is different from GMCT. In the case of EPL, the downstream pathways that translate MR activation into tissue inflammation, fibrosis, and dysfunction are still being elucidated (30). Recent studies using cell-selective MR-null or MR-overexpressing mice indicate that selective regulation by the MR of matrix metallopeptidase 2/matrix metallopeptidase 9 activity and the transforming growth factor (TGF)-β–connective tissue growth factor profibrotic pathway in cardiomyocytes may be potential mechanisms for the cardioprotective effects of the genetic or pharmacologic loss of MR signaling (30). Significant up-regulation of the TGF-β–connective tissue growth factor inhibitor decorin in ventricular cardiomyocytes from MR-null mice suggests that lower collagen levels may reflect an increase in inhibitors of the fibrotic process (30). Such effects have yet not been demonstrated in atrial myocytes.
On the other hand, we have shown previously that GMCT reduces both Gal-3 and TGF-β1–induced sheep atrial fibroblast migration and proliferation in vitro (8). In addition, a low dose of GMCT applied intravenously to sheep twice per week prevented the increase in serum P3NP seen during progression to persistent AF, and also mitigated atrial dilation, myocyte hypertrophy, and fibrosis and reduced the rate of DF increase. Moreover, TGF-β1 up-regulates in the atria of persistent AF sheep, but GMCT-treated animals had significantly less TGF-β1-Smad2/3 signaling pathway activation and expression of SMA and COLIII than did saline-treated animals. Similar to TGF-β1, platelet-derived growth factor also mediates cardiac fibrosis (31). Recent data showed that myofibroblast release of the platelet-derived growth factor AB isoform reduced atrial ICaL, shortened APD, and produced calcium handling dysfunction in cultured atrial cardiac myocytes (32). These alterations are consistent with the electrical remodeling that has been shown to occur in myocytes during AF (16), and that was mitigated by GMCT but not EPL.
Nevertheless, EPL treatment did reduce the AF burden, prolonged the time to 12h-AF, and increased the number of sheep resistant to persistent AF (Figure 6). Such results suggest that, even without modifying electrical remodeling during AF progression, reducing structural remodeling is beneficial. Moreover, by preventing dilation and interstitial fibrosis throughout the atria, EPL treatment reduced the heterogeneity of the anatomical substrate and allowed the AF sources to evolve over simpler trajectories (Figure 5A). This, together with the previously demonstrated mitigation of electrical remodeling by Gal-3 inhibition, suggests the possibility that adding adjuvant upstream EPL therapy to concomitant traditional antiarrhythmic therapy might increase the possibility of substantially reducing AF burden in AF patients.
It is unknown whether EPL affected AF initiation by modulating focal atrial ectopic discharges or PV arrhythmogenicity, which is critical in the genesis and maintenance of human AF (33). The mechanisms of AF in the sheep model and human patients with AF may have nuanced differences. In the sheep, intense burst pacing is likely to be more aggressive compared with intrinsic AF-initiating events during the natural progression of paroxysmal to persistent AF in humans, where AF reinitiation may be much more infrequent. However, the fibrosis level achieved in the sheep model at 7 days persistent AF is substantially lower compared with human persistent AF (8,34). Another limitation is that although EPL can benefit patients with mild-to-moderate arterial hypertension (35), we have not evaluated the effects on arterial blood pressure in our model. Importantly, except for comparing the effects of EPL versus SP, the experimental conditions were practically the same as in the previous 2 papers (8,16). Thus, we have used data from 6 sham-operated sheep from those studies to provide a control reference. As discussed in Figure 1, end-systolic RA and LA areas in the sham-operated group are visibly smaller than in persistent AF sheep groups with or without EPL treatment. Similarly, the lengths of RA and LA myocytes from the sham-operated group were consistently smaller than those from the EPL- and SP-treated persistent AF groups. Nevertheless, we acknowledge this use of historical sham-operated control animals as a potential limitation of our study. Finally, the mechanisms underlying AF may include not only electrical and structural factors, but also inflammation and oxidative stress. EPL may mitigate inflammation and reactive oxygen species, but we have not investigated them in our model.
The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.
COMPETENCY IN MEDICAL KNOWLEDGE: Aldosterone contributes to atrial dilation and fibrosis in patients with AF. EPL reduces the incidence of AF in patients with systolic HF. In a sheep model, the MR blocker mitigates fibrosis and atrial dilation, inhibits inducible AF and reduces the electrical complexity of AF, and decreases the burden of AF, but slows the progression to persistent AF inconsistently, without affecting the atrial electrical remodeling that leads to perpetuation of AF.
TRANSLATIONAL OUTLOOK: Although addition of an MR antagonist like EPL to antiarrhythmic therapy might help maintain sinus rhythm by preventing progression to persistent AF, more effective upstream interventions are needed to prevent the atrial electrical remodeling that underlies persistent and permanent AF.
The authors thank Cicero Willis, MD, Christopher Zerr, Patrick Wolfer, Rahul Mehta, Bharath Jakka, Danillo Z. de O. Souza, Sicong Wang, and Daniel Garcia Iglesias for their assistance in the experiments. They also thank St. Jude Medical and Medtronic for assistance with implantable devices.
This work was supported in part by National Heart, Lung, and Blood Institute R01 grant no. HL122352 National Institutes of Health/National Heart, Lung, and Blood Institute (Dr. Jalife); the Leducq Foundation Transatlantic Network of Excellence Program on “Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation” (Drs. Jalife and Berenfeld); and the University of Michigan Health System–Peking University Health Science Center Joint Institute for Translational and Clinical Research project “Molecular Mechanisms of Fibrosis and the Progression from Paroxysmal to Persistent Atrial Fibrillation” (Dr. Jalife). Dr. Takemoto was supported by the Uehara Memorial Foundation and a postdoctoral fellowship from the American Heart Association (14POST18220000). Dr. Salvador-Montañés was supported by the Martin Escudero Foundation. Dr. Berenfeld has served as the scientific officer for, owns equity in, and is the co-founder of Rhythm Solutions Inc.; received research grant support from Medtronic and Abbott; received honoraria from Boston Scientific; served as a consultant for Acutus Medical; and served as an R&D officer for Volta Medical. Dr. Jalife has served on the scientific advisory board of Abbott EP; and received research grant support from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- first 7-day persistent atrial fibrillation episode
- 11β-hydroxysteroid dehydrogenase type 2
- first 12-h atrial fibrillation episode
- atrial fibrillation
- action potential duration
- collagen III
- dominant frequency
- galactomannan GM-CT-01
- heart failure
- L-type calcium current
- inward rectifier potassium ion channel
- left atrium/atrial
- mineralocorticoid receptor
- mineralocorticoid receptor blocker
- procollagen type III N-terminal propeptide
- right atrium/atrial
- smooth muscle actin
- sugar pill
- transforming growth factor
- Received September 2, 2017.
- Accepted October 3, 2017.
- 2017 American College of Cardiology Foundation
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